Remedies for drug addiction

ABSTRACT

A remedy for drug dependence in which the active ingredient is an opioid κ receptor agonist in which the typical compound is represented by the following formula.  
                 
 
     An opioid κ receptor agonist in accordance with the present invention is different from a conventional symptomatic treatment manner for the drug dependence. The opioid κ receptor agonist in accordance with the present invention is a promising remedy for drug dependence with little adverse effects which affects expression mechanism of a reward effect so as to inhibit development both psychic dependence and physical dependence.

TECHNICAL FIELD

[0001] The present invention relates to a remedy for drug dependence. Inaddition, the present invention relates to a dopamine-release inhibitor,in which dopamine is heavily associated with drug dependence.

BACKGROUND ART

[0002] When a person repeatedly take a natural substance such as opium,cocaine, or marijuana, or takes a specific drug such as heroin,barbiturates, or stimulants, it is impossible to suddenly withhold thedrug. Then, their major goal in life tends to focus on obtaining thesesubstances and drugs. In addition, brutal crimes may be provoked.Moreover, serious incidents, which affect the state of the nation, mayalso be provoked. There is substantially the same underlying cause inthese problems of drug abuse as in habituation to consuming commonsubstances, for example, alcohol or tobacco.

[0003] World Health Organization (WHO) defines both drug dependence anddrug abuse. That is, drug dependence is defined as follows: “A state,psychic and sometimes also physical, resulting from the interactionbetween a living organism and a drug, characterized by behavioural andother responses that always include a compulsion to take the drug on acontinuous or periodic basis in order to experience its psychic effects,and sometimes to avoid the discomfort of its absence.” Drug dependenceis further classified as a state of psychic dependence on a drug, thatis, psychic dependence, or a state in which a body is adapted toexisting the drug, that is, physical dependence.

[0004] The WHO classifies drugs which become addictive into nine groups,that is, 1. alcohol, 2. amphetamines, 3. barbiturates, 4. marijuana, 5.cocaine, 6. hallucinogens, 7. khat, 8. opiates, and 9. organic solvents.All the drugs classified into the nine groups, to which dependence maybe developed, also show psychic dependence. In addition, three groups,that is, opiates, barbiturates, and alcohol, may be accompanied byphysical dependence. At present, among these drugs which developdependence, opiates, barbiturates, cocaine, and amphetamines areavailable for clinical use.

[0005] With respect to international laws relevant todependence-producing drugs, there are the “Single Convention Treaty onNarcotic Drugs” (1961) and the “The Convention on PsychotropicSubstances” (1971). Under the above-mentioned two treaties, allcountries are to make a concerted effort to conduct strict inspectionsof international distribution of narcotics and prevent narcotics frombeing illicitly distributed. As drug abuse expands throughout the world,international regulation becomes stricter. Recently, drugs capable ofbeing abused have increased both in kind and in variety. On the otherhand, since exchange of goods and travel have been internationallyincreased and an information network has been developed, cases ofpsychotropic drug abuse have increased in addition to cases ofnarcotics, marijuana, and stimulant abuse. In addition, the drug abuseepidemic area is also spreading throughout the world. For example,recently, narcotics abuse has significantly increased in countries inNorth America, Central and South America, Southeast Asia, Middle East,and Europe. In particular, the cocaine abuse problem has become a deepsocial ill in South America, North America, Europe and the like. On theother hand, the stimulants abuse problem has also spread in Japan, NorthAmerica, and Europe. Furthermore, at present, other psychotropic drugabuses have also increased in these countries.

[0006] With respect to a remedy for drug dependence, particular drugsare not usually applied other than drugs used for symptomatic treatment.The main treatment is psychotherapy which is aimed at self-awareness,replacing a dependence-producing drug with a drug which is lessdependent, or gradually-decreasing drug treatment. With respect tosymptomatic treatment, β-blocker such as diazepam and flunitrazepam, andshort-acting barbiturates have been initially used for treatment foracute toxipathy. An antipsychotic agent such as haloperidol orphenotiazines has been used for treatment of acute psychoses. However,the items of concern involve adverse effect such as psychogenesispeculiar to central nervous system sedatives in treatments using drugssuch as diazepam, flunitrazepam, or barbiturates. The items of concerninvolve adverse effects such as psychogenesis peculiar to psychotropicdrugs in treatment using drugs such as haloperidol or phenotiazines, sothat there is the possibility that drug dependence is replaced bypsychotropic drug dependence. (Alcohol and Drug Dependence, BasicResearch and Clinical Research, Kenshirou Oohara, Sakutarou Tadokoro(Kaneharasyuppan); Drug Dependence, Mitsumoto Satou, Susumu Fukui(Sekaihokentuusinsya)).

[0007] A drug reaction in which after the drug is given to a livingorganism, drug-seeking behavior or drug-taking behavior are morefrequently induced, is defined as a reinforcing effect or a rewardeffect. These effects caused by the dependence-producing drugs areclosely related to an intracerebral dopamine nervous system. Theintracerebral dopamine nervous system is roughly classified into twosystems, that is, a nigrostriatal system and a mesolimbic system whichprojects from an ventral tagmental area to a nucleus accumbens. Therehave been many reports which indicate the reinforcing effect or thereward effect is related to the mesolimbic system.

[0008] For example, cocaine, that is a central nervous system stimulant,affects neurosynapses in the nucleus accumbens so as to acceleratedopamine release from dopamine neuroterminals and to inhibit the uptakethereof, so that an amount of dopamine which binds to dopamine receptorsincreases and nerve activities are facilitated. Therefore, onset ofpsychic dependence seems to be triggered. On the other hand, sinceopioid κ receptor agonists inhibit dopamine release in the nucleusaccumbens (Japanese Journal of Pharmacology. 109: 165-173, 1997), theopioid κ receptor agonists may suppress the reward effect of cocaine andhold promise as a remedy for psychic cocaine dependence. At present,opioid κ receptor agonists, however, have not been applied in practicaluse for a remedy for cocaine dependence.

[0009] In addition, with respect to the relationship between opiates andtheir reward effect in drug dependence, it is known that opiates notonly have analgesic activity but also function as a chemical mediatorfor the reward effect. The opioid receptors are classified into μ, δ,and κ receptors. Among them, it was initially reported that μ receptoragonists such as morphine showed the reward effect (T. Suzuki et al.,Eur. J. Pharmacol. 205, 85, 1991). It has been reported that μ or δreceptor agonistic endogenous opioid peptides such as β-endorphins andenkephalins also show the reward effect (T. Suzuki et al., Jpn. J.Pharmacol. 66, 131, 1994).

[0010] Furthermore, opioid receptors are known to relate to a dopaminenervous system. The opioid μ receptors are distributed in high densityin a ventral tegmental area in which cell sonata of the mesolimbicsystem exist, so that they inhibit an inhibitory γ-aminobutyric acid(GABA) nervous system, that is, interneurons, and stimulate themesolimbic system. As a result, it is suggested that when a μ receptoragonist is systemically administered or microinjected into the ventraltegmental area, dopamine release in the projected nucleus accumbensseems to be significantly increased. On the other hand, δ, and κ opioidreceptors are known to be distributed in high density in the projectedarea, that is, nucleus accumbens in the mesolimbic system. When δ opioidreceptors are activated, similarly to μ opioid receptors, they seem toinhibit the inhibitory GABA nervous system, that is, interneurons, andto facilitate dopamine release in the nucleus accumbens. In contrast, κreceptor agonists do not show the reward effect in a drugself-administration (T. Suzuki et al., Brain Res. 602, 45, 1993). Asdescribed above, it is reported that when a κ receptor agonist such asU-50488H which activates κ receptors is administered, dopamine releasefrom the nucleus accumbens is inhibited (Japanese Journal ofPharmacology. 109: 165-177, 1997). In addition, animal tests show that-the reward effect induced by μ or δ receptor agonists is inhibited by κreceptor agonists such as U-50488H (M. Funada et al., Neuropharmacology,32, 1315, 1993). That is, activation of κ receptors enhances ananalgesic effect of μ or δ receptor agonists, but inhibits the rewardeffect. On the basis of these facts, opioid κ receptor agonists seem tobe promising remedies for psychic dependence to opioid μ receptoragonists. Furthermore, it is reported that opioid κ receptor antagonistsenhance development of physical dependence, but certain opioid κreceptor agonists inhibit development of physical dependence (Suzuki, T.et al., Eur. J. Pharmacol. 213, 91, 1991). At present, opioid κ receptoragonists, however, have not been adapted to remedies for opioid μreceptor agonists dependence and also have not been applied in practicaluse.

[0011] In a reported case of opioids and nicotine dependence (tobaccoaddiction), naloxone, that is, a narcotic antagonist (μ receptorantagonist), is effective for a reduction in intake of tobacco ofchronic smokers for three hours in a double blind test and a cross-overtest with a drug and its placebo (Karras, A. et al., Life Science, 27,1541, 1980). In contrast, it is reported that naloxone accelerates awithdrawal syndrome in rats with nicotine dependence, and morphine (a μreceptor agonist) inhibits the withdrawal syndrome after anadministration of nicotine (Malin, D. H. et al., Psychopharmacology,112, 339, 1993). In addition, it is reported that nicotinic receptorsexist at terminals of a dopamine nervous system in the nucleusaccumbens, and relate to facilitation of dopamine release (Di Chiara, G.et al., Natl. Acad. Sci. USA, 85, 5274, 1988). Furthermore, it isreported that a reduction in the amount of dopamine in the nucleusaccumbens follows the cessation of the administration of nicotine torats with nicotine dependence (Fung, Y. K. et al., J. Pharm. Pharmacol.,41, 66, 1989). In contrast, inhibitory activity against nicotinedependence of κ receptor agonists including dynorphin which is anendogenous opioid peptide having κ receptor agonistic activity,particularly inhibitory activity against physical dependence has notbeen clear.

[0012] In addition, there have been many reports that psychic dependenceon a drug such as barbiturates, benzodiazepines which are centralnervous system sedatives, amphetamine, methamphetamine, and the likewhich are stimulants, phencyclidine which is a hallucinogen, and alcoholis controlled by a mechanism of dopamine increase (Yanagita T., NipponYakugaku Zasshi—Folia Pharmacologica Japonica. 100 (2): 97-107, 1992Aug.; Samochowiec J., Annales Academiae Medicae Stetinensis. 40: 195-217(1994); Kuperman D I. et al., Brain Research. 771 (2): 221-7 (1997);Heron C. et al. European Journal of Pharmacology. 264 (3): 391-8 (1994);Saad S F. et al. Journal of Pharmacy & Pharmacology. 49 (3): 322-8(1997); Costall B. et al., Arzneimittel-Forschung. 42 (2A): 246-9(1992)). On the basis of the above-described facts, drugs havingactivity to inhibit dopamine release from the nucleus accumbens mayinhibit the reward effect caused by these dependence-producing drugs andmay be a promising remedy for psychic dependence.

[0013] In addition, existing highly selective κ receptor agonists suchas U-50488H prove not to develop drug dependence which is acharacteristic of morphine or the like having reactivity to a μ receptor(T. Suzuki et al., Eur. J. Pharmacol., 205, 85, 1991).

[0014] An object of the present invention is to provide a remedy fordrug dependence with little adverse effects, which depresses not onlyonset of psychic dependence but also physical dependence due tocontrolling the expression mechanism of the reward effect ofdependence-producing drugs in a treatment for drug dependence caused bycocaine, opioid μ agonists, nicotine, alcohol, stimulants, barbiturates,benzodiazepines, or hallucinogens. The above-mentioned treatment isdifferent from the conventional symptomatic treatments.

DISCLOSURE OF INVENTION

[0015] The present invention provides a remedy for drug dependence inwhich the active ingredient is an opioid κ receptor agonist. Inaddition, the present invention also provides a dopamine-releaseinhibitor in which the active ingredient is an opioid κ receptoragonist.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 and FIG. 2 show inhibitory effects of opioid κ receptoragonists against development of psychic dependence induced by an opioidμ receptor agonist.

[0017]FIG. 3 shows inhibitory effects of an opioid κ receptor agonistagainst development of psychic dependence induced by an opioid μreceptor agonist, and a result of an antagonism test on an opioid κreceptor atagonist.

[0018]FIG. 4 shows effects of an opioid κ receptor agonist on analoxone-induced withdrawal syndrome (a weight reduction).

[0019]FIG. 5 and FIG. 6 show inhibitory effects of opioid κ receptoragonists against development of psychic dependence induced by cocaine.

[0020]FIG. 7 shows inhibitory effects of an opioid κ receptor agonistagainst development of psychic dependence induced by cocaine.

[0021]FIG. 8 shows a drug discrimination effect of opioid κ receptoragonist.

[0022]FIG. 9 shows an effect of an opioid κ receptor antagonist on aninhibition of cocaine discrimination by an opioid κ receptor agonist.

[0023]FIG. 10 shows inhibitory effects on a mecamylamine-inducednicotine withdrawal syndrome by an opioid κ receptor agonist.

[0024]FIG. 11 shows inhibitory effects on dopamine release by an opioidκ receptor agonist.

BEST MODE FOR CARRYING OUT THE INVENTION

[0025] The present invention includes a remedy for nicotine dependencein which an active ingredient is an opioid κ receptor agonist. In thiscase, the opioid κ receptor agonist is a compound which is selectivetowards the opioid κ receptor even if the compound has any specificchemical structure. That is, guinea-pig ileum (GPI) and mouse vasdeference (MVD) tests are performed in order to assess agonisticactivity on an opioid receptor (assessment of an inhibitory effect onconstriction induced by electric stimulation of guinea-pig ileum andmouse vas deference). Then, the same procedure is performed in thepresence of an opioid receptor antagonist, in which the antagonist isselective towards μ, δ, or κ receptor, so as to calculate Ke values.When the Ke values of the receptors are compared with each other, acompound, in which Keμ is greater than Keκ and Keδ is simultaneouslygreater than Keκ, is more selective towards a κ receptor than to a μ anda δ receptor.

[0026] Specifically, the compound is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (I):

[0027] wherein . . . is a double bond, or a single bond; R¹ is an alkylgroup having from 1 to 5 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkylgroup having from 7 to 13 carbon atoms, an alkenyl group having from 4to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5carbon atoms; R₂ is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or 0; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ may beidentical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group may be substituted by one ormore substituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupmay be replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon may be substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the acyclicunsaturated hydrocarbon maybe replaced with carbonyl groups), or astraight-chain or branched-chain saturated or unsaturated hydrocarboncontaining from one to five thioether, ether, and/or amino bonds andhaving from 1 to 14 carbon atoms (wherein no hetero atoms are bondeddirectly to A, and one to three methylene groups of the hydrocarbon maybe replaced with carbonyl groups); and R⁵ is a hydrogen atom or anorganic group having a basic skeleton selected from the group consistingof the following formulas:

Organic Groups Represented by R⁵

[0028] wherein the organic group may have at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup; R⁶ is a hydrogen atom; R⁷is a hydrogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, or an alkanoyloxy grouphaving from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S—together; R⁸ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms. Andoptionally the compound is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (II):

[0029] wherein R denotes two hydrogen atoms, or —O—CH₂CH₂CH₂—; X and Yare, independently of each other, a hydrogen atom or a chlorine atom; Zis O or S. And optionally the compound is an opioid κ receptor agonistor pharmacologically acceptable acid-addition salts thereof representedby the general formula (III):

[0030] wherein X is a hydrogen atom, a chlorine atom, or atrifluoromethyl group; Y is a hydrogen atom or a chlorine atom; Z isCH₂, —OCH₂CH₂O—, or NCO₂CH₃. And optionally the compound is an opioid κreceptor agonist or pharmacologically acceptable acid-addition saltsthereof represented by the general formula (IV):

[0031] wherein X and Y are, independently of each other, a hydrogen atomor a chlorine atom; Z is CH₂, O or S. And optionally the compound is anopioid κ receptor agonist or pharmacologically acceptable acid-additionsalts thereof represented by the general formula (V):

[0032] wherein X and Y are, independently of each other, a hydrogen atomor a chlorine atom.

[0033] In addition, the present invention includes a remedy for nicotinedependence, a remedy for cocaine dependence, a remedy for opioid μreceptor agonist dependence, and a dopamine-release inhibitor in-whichthe active ingredient is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (I):

[0034] wherein . . . is a double bond, or a single bond; R¹ is an alkylgroup having from 1 to 5 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkylgroup having from 7 to 13 carbon atoms, an alkenyl group having from 4to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5carbon atoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ may beidentical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group may be substituted by one ormore substituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupmay be replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon may be substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the acyclicunsaturated hydrocarbon may be replaced with carbonyl groups), or astraight-chain or branched-chain saturated or unsaturated hydrocarboncontaining from one to five thioether, ether, and/or amino bonds andhaving from 1 to 14 carbon atoms (wherein no hetero atoms are bondeddirectly to A, and one to three methylene groups of the hydrocarbon maybe replaced with carbonyl groups); and R⁵ is a hydrogen atom or anorganic group having a basic skeleton selected from the group consistingof the following formulas:

Organic Groups Represented by R⁵

[0035] wherein the organic group may have at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup; R⁶ is a hydrogen atom; R⁷ is a hydrogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, or an alkanoyloxy grouphaving from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S—together; R⁸ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms.

[0036] In the compound represented by the general formula (I) among theκ receptor agonists in accordance with the present invention, R¹ ispreferably an alkyl group having from 1 to 5 carbon atoms, acycloalkylmethyl group having from 4 to 7 carbon atoms, acycloalkenylmethyl group having from 5 to 7 carbon atoms, a phenylalkylgroup having from 7 to 13 carbon atoms, an alkenyl group having from 4to 7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having from1 to 5 carbon atoms, or a thiophene-2-yl-alkyl group having from 1 to 5carbon atoms; and R¹ is particularly preferably a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup.

[0037] R² is preferably a hydrogen atom, a hydroxy group, a nitro group,an acetoxy group, a methoxy group, a methyl group, an ethyl group, apropyl group, an amino group, a dimethylamino group, an acetylaminogroup, or a benzoylamino group; and R² is particularly preferably ahydrogen atom, a hydroxy group, an acetoxy group, or a methoxy group.

[0038] R³ is preferably a hydrogen atom, a hydroxy group, an acetoxygroup, or a methoxy group, and is particularly preferably a hydroxygroup, an acetoxy group, or a methoxy group.

[0039] A is preferably —XC(═Y)— (wherein X is NR⁴, S, or O; Y is O; andR⁴ is a hydrogen atom, or a straight-chain or branched-chain alkyl grouphaving from 1 to 5 carbon atoms), —XC—(═Y)Z—, —X—, or —XSO₂— (wherein Xis NR⁴; Y is O or S; Z is NR⁴ or O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms). Specifically, A is —NR⁴C(═O)—, —NR⁴C(═S)—, —NR⁴C(═O)O—, —NR⁴C(═O) NR⁴—, —NR⁴C(═S) NR⁴—, —NR⁴C(═O)S—, —OC(═O)—, —OC(═O)O—, —SC(═O)—,—NR⁴—, —O—, —NR⁴SO₂—, —OSO₂— or the like. Among them, A is preferably—NR⁴C(═O)—, —NR⁴C(═S)—, —NR⁴C (═O)O—, —NR⁴C(═O)NR⁴—, —NR⁴C (═S)NR⁴—, or—NR⁴SO₂—; and more preferably —NR⁴C(═O)— or —NR⁴C(═O)O—.

[0040] R⁴ is preferably a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, and isparticularly preferably a straight-chain or branched-chain alkyl grouphaving from 1 to 5 carbon atoms, with a methyl group, an ethyl group, apropyl group, a butyl group or an isobutyl group being the mostpreferred.

[0041] B is preferably a straight-chain alkylene group having from 1 to10 carbon atoms, —(CH₂)_(n)—C(═O)— (n═1to 4), —CH═CH— (CH₂)_(n)— (n═0 to4), —C≡C—(CH₂)_(n) (n═0 to 4), —CH₂—O—, —CH₂—S—, —(CH₂)₂—O—CH₂—, or—CH═CH—CH═CH—(CH₂)n- (n═O to 4), and more preferably a straight-chainalkylene group having from 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH₂—O—or —CH₂—S—, with a straight-chain alkylene group having from 1 to 3carbon atoms, —CH═CH—, or —C≡C— being most preferable.

[0042] R⁵ is preferably a hydrogen atom or an organic group having anyone of the following fundamental structures:

Organic Groups Represented by R⁵

[0043] wherein the organic group may be substituted by a substituentsselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an amino group, a nitrogroup, a cyano group, a isothiocyanato group, a trifluoromethyl group, atrifluoromethoxygroup, and a methylenedioxy group. Among them, ahydrogen atom, a phenyl group, 4-methylphenyl, 3-methylphenyl,2-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl,3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 4-hydroxyphenyl,3-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-fluorophenyl, 3-fluorophenyl,2-fluorophenyl, 3,4-difluorophenyl, perfluorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4,5-trichlorqphenyl, 2,4,6-trichlorophenyl, 4-bromophenyl,3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,2-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 2-aminophenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3,4-methylenedioxyphenyl, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl,cyclopentyl or cyclohexyl are particularly preferred. Of course R⁵ isnot limited to these. These opiate κ receptor agonists represented bythe general formula (I) can be produced, for example, by the methoddisclosed in Japanese Patent No.2525552.

[0044] Among the κ receptor agonists in accordance with the presentinvention represented by the general formula (II), preferred aretrans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]acetamide; trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzo [b]thiophene-4-acetamide; (5β, 7β,8α)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5]dec-8-yl] benzeneacetamide; (5β, 7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5] dec-8-yl] benzo [b]furan-4-acetamide; and (5β, 7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5] dec-8-yl]benzeneacetamide. The κ receptor agonists represented by the generalformula (II) can be produced, for example, by the methods according toSzmuszkovicz, J. et al., J. Med. Chem., 25, 1125 (1982); Horwell, D. C.,et al., U.S. Patent Appl., 558737 (1983); Szmuszkovicz, J. et al., Eur.Patent Appl., EP126612 (1984); Halfpenny, P. R., et al., J. Med. Chem.,33, 286 (1990); or the like.

[0045] Among the κ receptor agonists in accordance with the presentinvention represented by the general formula (III), preferred are methyl4-[(3,4-dichlorophenyl) acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; 1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl) methyl] piperidine; 1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl) methyl] piperidine; and1-[(3,4-dichlorophenyl) acetyl]-4,4-ethylenedioxy-2[(1-pyrrolidinyl)methyl] piperidine. The κ receptor agonists represented by the generalformula (III) can be produced by the methods according to Naylor, A., etal., J. Med. Chem., 36, 2075 (1993); Vecchietti, V., et al., J. Med.Chem., 34, 397 (1991); Eur. Patent Appl. EP232612 (1987), EP260041(1988), EP275696 (1988); Scopes, D.I.C., et al., J. Med. Chem., 35, 409(1992) or the like.

[0046] Among the κ receptor agonists in accordance with the presentinvention represented by the general formula (IV), preferred are3-(1-pyrrolidinylmethyl)-4-[5,6-dichloro-1-indanecarbonyl]-tetrahydro-1,4-thiazine.These κ receptor agonists represented by the general formula (IV) can beproduced, for example, by the method disclosed in WO 94/05646.

[0047] Among the κ receptor agonists in accordance with the presentinvention represented by the general formula (V), preferred are2-(3,4-dichlorophenyl)-N-methyl-N-[1-phenyl-2-(1-pyrrodinyl) ethyl]acetamide. These κ receptor agonists represented by the general formula(V) can be produced, for example, by the method according to Barlow, J.J., et al., J. Med. Chem., 34, 3149(1991).

[0048] Among the pharmacologically acceptable acid-addition salts of theopioid κ receptor agonists described above are inorganic acid salts,such as hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides,and phosphates; organic carboxylates, such as acetates, lactates,citrates, oxalates, glutarates, malates, tartrates, fumarates,mandelates, maleates, benzoates, and phthalates; and organic sulfonates,such as methanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates, and camphorsulfonates. Among them, hydrochlorides,hydrobromides, phosphates, tartrates, and methanesulfonates arepreferred, but of course they are not limited to those compounds.

[0049] The opioid κ receptor agonists in accordance with the presentinvention inhibit dopamine release from the dopamine nervous system inthe mesolimbic system which projects from a ventral tagmental area tothe nucleus accumbens, so that they are useful as dopamine-releaseinhibitors. Dopamine is closely related with drug dependence.Dependence-producing drugs such as cocaine; opioid μ agonists; nicotine;alcohol; stimulants; central nervous system sedatives, for example,barbiturates, benzodiazepines, and the like; and hallucinogens induce areward effect due to an increase in dopamine release from the dopaminenervous system in the mesolimbic system, so that the onset of drugdependence is triggered. Therefore, the opioid κ receptor agonists inaccordance with the present invention are useful for treating drugdependence induced by drugs which facilitate dopamine release.

[0050] The drug dependence dealt by the present invention representspsychic dependence and physical dependence induced bydependence-producing drugs. Examples of the diseases which can betreated by the remedy in accordance with the present invention arecocaine dependence, opioid μ receptor agonist dependence, nicotine(tobacco) dependence, alcohol dependence, stimulant dependence, centralnervous system sedative dependence, and hallcinogen dependence.

[0051] Examples of drugs which induce the above-mentioned drugdependences are opioid μ receptor agonists such as morphine, heroin, andcodeine; stimulants such as amphetamine and methamphetamine; centralnervous system sedatives such as the barbiturates, for example,phenobarbital, pentobarbital, thiopental, and the like, and thebenzodiazepines, for example, diazepam, lorazepam, oxazepam,chlordiazepoxide, and the like; and hallucinogens such as phencyclidine.Of course, however, they are not limited to those compounds.

[0052] Therapeutic effects of the opioid κ receptor agonists inaccordance with the present invention against drug dependence can beassessed by a conditioned place preference method (a CPP method) and adrug discrimination test which are used for assessing psychicdependence, assessment a withdrawal syndrome due to administration of anantagonist which is used as a method for assessing physical dependence,or the like (Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990);Spyraki, C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988); Yanagita, T., Psychopharmacology, 27, 503(1975); Deueau, G. A. et al., Psychopharmacology, 16, 30 (1969); TsutomuSuzuki, Molecular Medicine, 32, 140 (1995); Maldonado, R. et al., J.Pharmacol. Exp. Ther., 261, 669 (1992)). A significant inhibitory effecton psychic dependence and physical dependence has been confirmed bythese tests.

[0053] After the opioid κ receptor agonists in accordance with thepresent invention have been purified to yield a purity which isappropriate for medical use and have passed the required safety tests,they can be orally or parenterally administered without additives or asmedical compositions including known pharmacologically acceptable acids,carriers, vehicles, and the like.

[0054] With respect to parenterally administrated composition, thecompounds in accordance with the present invention can be administeredusing a liquid carrier such as sterilized water without pyrogens,sterilized ethyl oleate without peroxides, anhydrous alcohol,polypropylene glycol, and mixtures thereof, which can be usually usedfor injection.

[0055] Pharmaceutical adjuvants suitable for an injection solution caninclude stabilizers, solubilizers, buffers, viscosity modifiers, andantioxidants. Examples of these adjuvants are ethanol,ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citratebuffers, and polyethylene oxide viscosity modifiers. Thesepharmaceutical preparations can be intramuscularly, intraperitoneally,or intravenously injected.

[0056] The compounds in accordance with the present invention can beorally administered as solid or liquid pharmaceutical compositionsaccompanied with a conventional solid or liquid compatible carrier. Thepharmaceutical composition which is orally administered can includebinders such as syrups, acacia gum, gelatin, sorbitol, tragacanth gum,polyvinyl pyrrolidone, or mixtures thereof, that is, conventionalingredients may be used,

[0057] Furthermore, the composition can include fillers such as lactose,mannitol, starch, calcium phosphate, sorbitol, methyl cellulose, ormixtures thereof.

[0058] In addition, the orally administrated composition can includelubricants such as magnesium stearate, high molecular weight polymerssuch as polyethylene glycol, high molecular weight fatty acids such asstearic acid, silica or additives such as starch, which facilitatedisintegration of solid pharmaceutical preparations, and lubricants suchas sulfuric acid lauryl sodium.

[0059] The orally administrated composition can be prepared as anyconventional forms such as tablets, capsules, lozenges, aqueous or oilsuspensions, emulsions, or powders which can be reconstituted usingwater or other proper solutions before use.

[0060] Solid or liquid constituents can include flavors, sweetenersand/or preservatives such as alkyl p-hydroxy benzoate. The liquidconstituents can, furthermore, include suspensions such as sorbitol,glucose, other sugar syrups, methyl cellulose, hydroxymethyl cellulose,carboxymethyl cellulose, or gelatin; emulsifiers such as lecithin orsorbitol monooleate; or a usual thickening agent. The liquidconstitutents can be, for example, encapsulated in a gelatin capsule.

[0061] The pharmaceutical composition in accordance with the presentinvention is most preferably available in units. In the above-mentionedconstitution, the pharmaceutical preparation is subdivided into unitdosages having an adequate dose of an active ingredient. A availableunit constitution can be prepared as a packaged pharmaceuticalpreparation having a package which includes a non-homogenized dose ofthe pharmaceutical preparation. The package may have constitution suchas tablets, capsules, powders, vials, or ampoules. The available unitconstitution may be capsules, cachets, tablets, pharmaceuticalcomposition as such, or optionally and properly packaged constitutionthereof.

[0062] The dosage is properly selected according to symptoms, age, bodyweight, and administration route. In adults, the daily dosage rangesfrom 0.001 mg to 1 g as an active ingredient, when it is injected, andthe daily dosage ranges from 0.005 mg to 3 g, when it is orallyadministered. In each case, the dosage can be administered once a day orseveral times a day.

EXAMPLES

[0063] The present invention is described in further detail below withreference to examples.

Example 1

[0064] Inhibitory effects of opioid κ receptor agonists againstdevelopment of psychic dependence induced by an opioid μ receptoragonist.

[0065] Inhibitory effects of the opioid κ receptor agonists againstdevelopment of psychic dependence induced by an opioid μ receptoragonist were examined by a conditioned place preference method (Suzuki,T. et al., Psychopharmacology, 102, 438-442 (1990); Spyraki, C., Thepsychopharmacology of dependence, p96, Oxford Medical Publications, NewYork (1988); hereinafter referred to as a CPP method). Morphine was usedas the opioid μ receptor agonist which developed psychic dependence. Onthe other hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan maleate (Compound 1) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-3-methylcinnamide)morphinan hydrochloride (Compound 2) were used as the opioid κ receptorselective agonists.

[0066] Animals used were Sprague Dawley strain (SD strain) male rats inthis experiment. Experiments used were CPP operant boxes having twocompartments colored white and black, respectively. In this experiment,animals were given conditioning training for a sensation effect on adrug and environments in the operant boxes (white and black) for sixdays. After the period for the conditioning training, tests were carriedout by placing the conditioned animals in the operant boxes withoutadministration of the drug. Drug dependence and drug aversion wereassessed from the periods in which the rats remained in the white orblack box during the test.

[0067] Accordingly, as shown in FIGS. 1 and 2, the periods, in which therats remained in the box conditioned by the drug, with administration ofmorphine alone (3 mg/kg, subcutaneously administration) wassignificantly prolonged compared with a control group to which thesolvent was administered. Therefore, development of dependence wasrecognized. In contrast, it was recognized that the periods in which therats remained was not significantly prolonged in the test groups whichwere given morphine in combination with Compound 1 or Compound 2compared with the control group. Therefore, it was clear that Compound 1and Compound 2 inhibited the development of drug dependence caused bymorphine, when they were subcutaneously given 0.1 mg/kg, respectively.In addition, it was recognized that the periods in which the ratsremained of the group given Compound 1 alone or that of Compound 2 alonewas not prolonged both in the drug-conditioned box and in thesolvent-conditioned box compared with the control group to which thesolvent was administered. Therefore, it was clear that these compoundsdid not develop psychic dependence and aversion.

[0068] In addition, in FIGS. 1 and 2, a symbol * represents a level ofsignificance of not more than 5%, thereby indicating statisticalsignificance.

Example 2

[0069] Inhibitory effects of an opioid κ receptor agonist againstdevelopment of psychic dependence induced by an opioid μ receptoragonist, and a result of an antagonism test on an opioid κ receptorantagonist.

[0070] Inhibitory effects of the opioid κ receptor agonist againstdevelopment of psychic dependence induced by an opioid μ receptoragonist were examined by a CPP method (Suzuki, T. et al.,Psychopharmacology, 102, 438-442 (1990); Spyraki, C., Thepsychopharmacology of dependence, p96, Oxford Medical Publications, NewYork (1988)). Morphine was used as the oploid μ receptor agonist whichdeveloped psychic dependence. On the other hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3) was used as the opioid κ receptorselective agonist. The same experimental procedure was performed as thatin Example 1.

[0071] Accordingly, as shown in FIG. 3, the periods in which the ratsremained in the box conditioned by the drug was significantly prolongeddue to the administration of morphine alone (5 mg/kg, subcutaneouslyadministration). Therefore, development of dependence was recognized. Incontrast, it was recognized that the periods in which the rats remainedwas significantly reduced in the test groups which were given morphinein combination with Compound 3 compared with the group to which morphinealone was administered. Therefore, it was clear that Compound 3inhibited the development of drug dependence caused by morphine, whenthey were subcutaneously given 0.1 or 0.03 mg/kg of Compound 3,respectively. Furthermore, the inhibitory effect caused by Compound 3was significantly antagonized by pretreatment with norbinaltorphimine(nor-BNI) (3 mg/kg), that is, an opioid κ receptor selective antagonist,so that it was clear that the inhibitory effect caused by Compound 3 ondrug dependence was mediated by the opioid κ receptor.

[0072] In addition, it was recognized that the periods in which the ratsremained in the group given Compound 3 alone was not prolonged both inthe drug-conditioned box and in the solvent-conditioned box comparedwith the control group to which the solvent was administered. Therefore,it was clear that the Compound 3 did not produce psychic dependence andaversion.

[0073] In FIG. 3, a symbol * represents a level of significance of notmore than 5%, and a symbol ** represents a level of significance of notmore than 1% with respect to the morphine alone treated group (5 mg/kg,subcutaneously administration), thereby indicating statisticalsignificance. Furthermore, a symbol ## represents a level ofsignificance of not more than 1% with respect to the morphine (5 mg/kg,subcutaneously administration) in combination with Compound 3 (0.03mg/kg, subcutaneously administration) treated group, thereby indicatingstatistical significance.

Example 3

[0074] Effects of an opioid κ receptor agonist on a naloxone-inducedwithdrawal syndrome (a weight reduction).

[0075] Inhibitory effects of the opioid κ receptor agonist ondevelopment of physical dependence induced by an opioid μ receptoragonist were examined (Tsutomu Suzuki, Molecular Medicine, 32, 140(1995); Maldonado, R. et al., J. Pharmacol. Exp. Ther., 261, 669(1992)). Morphine was used as the opioid μ receptor agonist whichdeveloped physical dependence. On the other hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3) was used as the opioid κ receptorselective agonist.

[0076] Animals used were ddY strain male mouse. Physical dependence wasdeveloped using an injection method. Morphine was repeatedly andsubcutaneously administered to the mouse twice a day for five days at adose ranging from 8 to 45 mg/kg, the dose being gradually increased.Naloxone (3 mg/kg) was subcutaneously administered two hours after thelast administration of morphine. Then, just after the administration ofnaloxone, a withdrawal syndrome was observed for 60 minutes. Compound 3was simultaneously administered with morphine.

[0077] Accordingly, as shown in FIG. 4 and Table 1, the withdrawalsyndrome was recognized in the mouse, to which morphine alone wasadministered, because of the naloxone administration. Therefore, it wasconfirmed that physical dependence-was developed by morphine. Thewithdrawal syndrome was relieved by the simultaneous administration ofCompound 3 in a dose-dependent manner. Incidence rates of jumping,shaking, and diarrhea were significantly decreased by administration ofCompound 3 at a dose of 0.03 mg/kg compared with the group to whichmorphine alone was administered. In addition, it was recognized thatboth Compound 3 groups administered at a dose of 0.01 or 0.03 mg/kgrevealed significant suppression of body weight reduction compared withthe morphine alone administered group. This result showed that theopioid κ receptor agonist inhibited development of physical dependenceinduced by the opioid p receptor agonist.

[0078] Table 1 Effects of an opioid κ receptor agonist on a withdrawalsyndrome induced by naloxone Numbers of mouse manifesting withdrawalsyndrome/ Numbers of total mouse Withdrawal Physiological Compound 3(mg/kg, s.c.) syndrome saline 0.003 0.01 0.03 Jumping 10/10  3/10  5/10 3/10* Wobbling 10/10  7/10  5/10  3/10* Rearing 10/10 10/10  7/10  8/10Diarrhea 10/10  7/10  6/10  3/10* Blepharoptosis 10/10 10/10 10/10 10/10Fore paw tremor 10/10  9/10 10/10  7/10

[0079] In FIG. 4, a symbol  represents the group which was givenmorphine alone, a symbol ◯ represents the group which was given morphinein combination with Compound 3 (0.003 mg/kg, subcutaneouslyadministration), a symbol Δ represents the group which was givenmorphine in combination with Compound 3 (0.01 mg/kg, subcutaneouslyadministration), and a symbol □ represents the group which was givenmorphine in combination with Compound 3 (0.03 mg/kg, subcutaneouslyadministration). A symbol * represents a level of significance of notmore than 5%, thereby indicating statistical significance.

Example 4

[0080] Inhibitory effects of opioid κ receptor agonists on developmentof psychic dependence induced by cocaine.

[0081] Inhibitory effects of the opioid κ receptor agonists ondevelopment of psychic dependence induced by cocaine were examined by aCPP method (Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990);Spyraki, C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988)).17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(3-methylphenyl)propiolamide]morphinan hydrochloride (Compound 4) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(methoxycinnamide)morphinan tartrate (Compound 5) were used as the opioid κ receptorselective agonists.

[0082] Animals used were Sprague Dawley strain (SD strain) male rats inthis experiment. Experiments used were CPP operant boxes having twocompartments colored white and black, respectively. In this experiment,animals were given conditioning training for a sensation effect on adrug and environments in the operant boxes (white and black) for sixdays. After the period for the conditioning training, tests were carriedout by placing the conditioned animals in the operant boxes withoutadministration of the drug. Drug dependence and drug aversion wereassessed from the periods in which the rats remained in the white orblack box during the test.

[0083] Accordingly, as shown in FIGS. 5 and 6, the periods, in which therats remained in the box conditioned by the drug, in the groupadministered cocaine alone (10 mg/kg, intraperitoneal administration)was significantly prolonged compared with that in a control group towhich the solvent was administered. Therefore, development of dependencewas recognized. In contrast, it was recognized that the periods in whichthe rats remained was not significantly prolonged in the test groupswhich were given cocaine in combination with Compound 4 or Compound 5compared with that in the control group which was given solvent.Therefore, it was clear that Compound 4 and Compound 5 inhibited thedevelopment of drug dependence induced by cocaine, when they weresubcutaneously given 0.1 mg/kg of Compound 4 and Compound 5,respectively. In addition, it was recognized that the periods in whichthe rats remained in the group given Compound 4 alone or that ofCompound 5 alone was not prolonged both in the drug-conditioned box andin the solvent-conditioned box. Therefore, it was clear that thesecompounds did not produce psychic dependence and aversion.

[0084] In addition, in FIGS. 5 and 6, a symbol * represents a level ofsignificance of not more than 5%, thereby indicating statisticalsignificance.

Example 5

[0085] Inhibitory effects of an opioid κ receptor agonist on developmentof psychic dependence induced by cocaine.

[0086] Inhibitory effects of the opioid κ receptor agonist ondevelopment of psychic dependence induced by cocaine was examined by aCPP method (Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990);Spyraki, C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988)).17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan maleate (Compound 1) was used as the opioid κ receptorselective agonist. The same experimental procedure was performed as thatin Example 4.

[0087] Accordingly, as shown in FIG. 7, the periods, in which the ratsremained in the box conditioned by the drug, in the group administeredcocaine alone (4 mg/kg, intraperitoneal administration) wassignificantly prolonged, so that development of dependence wasrecognized. In contrast, it was recognized that the period in which theanimals remained was significantly decreased in the test group whichwere given cocaine in combination with Compound 1 compared with that inthe control group which was given cocaine alone. Therefore, it was clearthat Compound 1 inhibited the development of drug dependence induced bycocaine, when it was intraperitoneally given 0.2 mg/kg.

[0088] In addition, it was recognized that the period in which the ratsremained in the group given Compound 1 alone was not prolonged both inthe drug-conditioned box and in the solvent-conditioned box comparedwith that in the control group which was given solvent. Therefore, itwas clear that the compound did not produce psychic dependence andaversion.

[0089] In addition, in FIG. 7, a symbol ** represents a level ofsignificance of not more than 1%, thereby indicating statisticalsignificance.

Example 6

[0090] Inhibitory effect of opioid κ receptor agonist on a drugdiscrimination test.

[0091] Rats were preliminarily trained for the drug discrimination test(Yanagita, T., Psychopharmacology, 27, 503 (1975); Deueau, G. A. et al.,Psychopharmacology, 16, 30 (1969)) by previously giving cocaine at adose of 10 mg/kg or physiological saline, in which an indicator isfeeding behavior with lever pressing.17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that, is, an opioid κ receptorselective agonist (10 μg/kg) was administered in combination withcocaine (each dose) to the rats, so that the drug discrimination testwas performed.

[0092] The results are shown in FIG. 8. Rates of feeding behavior withlever pressing were significantly decreased in the groups which wereadministered cocaine at a dose of 1.25, 2.5, or 5 mg/kg in combinationwith Compound 3 compared with that in the solvent control group whichwas administered cocaine in combination with physiological saline.Accordingly, it was revealed that Compound 3 inhibited manifestation ofa reward effect induced by cocaine, so that Compound 3 is suggested tobe a promising remedy for cocaine dependence.

[0093] In FIG. 8, a symbol  represents the group which was givenphysiological saline in combination with cocaine, and a symbol ◯represents the group which was given Compound 3 (0.01 mg/kg) incombination with cocaine. A symbol * represents a level of significanceof not more than 5%, thereby indicating statistical significance.

[0094] Furthermore, it was clear that when Compound 3 (20 μg/kg) wasgiven in combination with cocaine (each dose), inhibitory effect ofcocaine discrimination was enhanced compared with the case in whichCompound 3 (10 μg/kg) was given. In addition, as shown in FIG. 9, whennor-BNI, that is, an opioid κ receptor antagonist was pretreated, ratesof feeding behavior with lever pressing were same as those in the groupgiven physiological saline in combination with cocaine. Thus, theinhibitory effect of cocaine discrimination of Compound 3 wasantagonized by the opioid κ receptor antagonist. These results showedthat the inhibitory effect of cocaine discrimination was manifested viathe opioid κ receptor, so that psychic dependence induced by cocainecould be inhibited by the opioid κ receptor agonist.

[0095] In FIG. 9, a symbol  represents the group which was givenphysiological saline in combination with cocaine, a symbol ◯ representsthe group which was given Compound 3 (0.02 mg/kg) in combination withcocaine, and a symbol □ represents the group which was given Compound 3(0.02 mg/kg) in combination with cocaine after the pretreatment ofnor-BNI. A symbol ** represents a level of significance of not more than1%, thereby indicating statistical significance.

Example 7

[0096] Inhibitory effects on a mecamylamine-induced nicotine withdrawalsyndrome by an opioid κ receptor agonist

[0097] Animals used were SD strain male rats in this experiment.Experiments used were CPP operant boxes. Experiments were performed byusing an aversive model in a nicotine withdrawal syndrome induced bymecamylamine, that is, a nicotine receptor antagonist. (Tsutomu Suzuki,Molecular Medicine, 32, 140 (1995); Suzuki, T. et al., Eur. J. Pharm.,314, 281 (1996); Maldonado, R. et al., J. Pharmacol. Exp. Ther., 261,669 (1992)). Mini-osmotic pump (Alzet 2001) injected with nicotine (1μl/hr, for seven days) was implanted under dorsal skin of the rats. Anaqueous solution at a concentration of 121.4 mg/ ml was prepared so thata nicotine dose was adjusted to 10 mg/kg/day. Then, the aqueous solutionwas filled into the mini-osmotic pump. The rats were given conditioningtraining by the following counter-balance method. In the morning of theseventh day after the implantation of the mini-osmotic pump,mecamylamine (1 mg/ml), that is, nicotine receptor antagonist orphysiological saline was subcutaneously injected. Then, the rats wereplaced in one compartment for 60 minutes. And then, in the evening ofthe same day, the opposite treatments were performed (physiologicalsaline was administered to the rats to which mecamylamine had beenadministered in the morning, and mecamylamine was administered to therats to which physiological saline was administered in the morning), andthe rats were placed in the other compartment for 60 minutes. Then,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that is, an opioid κ receptorselective agonist was subcutaneously administered 30 minutes before themecamylamine treatment. On the next day of the conditioning training(the eighth day), tests were performed. The periods in which the ratsremained in each compartment colored white or black were measured for 15minutes.

[0098] The results were shown in FIG. 10. A negative value indicates theperiod in which rats escaped from the compartment conditioned bysucutaneous injection of mecamylamine. It was shown that the greater thenegative value means the stronger the aversive effect at the nicotinewithdrawal. The aversive effect induced by mecamylamine was inhibited bythe pretreatment with Compound 3 (10 or 30 μg/kg) in a dose dependentmanner. In addition, it was recognized that the pretreatment of Compound3 (30 μg/kg) significantly inhibited the aversive effect compared withthe aversive effect in the group pretreated with physiological saline.That is, the physical dependence developed by nicotine was inhibited.

[0099] In FIG. 10, a symbol * represents a level of significance of notmore than 5%, thereby indicating statistical significance.

Example 8

[0100] Inhibitory effects on dopamine release by an opioid κ receptoragonist.

[0101] Animals used were SD strain male rats at an age of at least sixweeks. After rats were killed by decapitation, the forebrains wereenucleated. The forebrains were longitudinally severed in the mediaddirection in Krebs-Ringer-Bicarbonate medium which were chilled incracked ice, and sliced with a tissue chopper at intervals of 500 μm.The nucleus accumbens areas were knocked through the slices containingthe nucleus accumbens using a punch having an inner diameter of 2 mm.After the nucleus accumbens were preincubated in theKrebs-Ringer-Bicarbonate medium under bubbling a gas containing O₂ at95% and CO₂ at 5% for 20 minutes, they were placed in a reflux apparatusso as to be 24 slices per a chamber, and refluxed with theKrebs-Ringer-Bicarbonate medium which were added with nomifensine at aconcentration of 10 μM for 30 minutes. Then, the reflux was performed ata rate of 0.25 ml/min. and samples were obtained at intervals of fiveminutes. After 20 minutes, and 60 minutes, 20 mM high K⁺ stimulationwere subjected for 10 minutes so as to facilitate dopanime release.17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that is, an opioid κ receptoragonist was dissolved in distilled water, diluted with the medium, andadded 20 minutes before the second stimulus. The amounts of dopamine inthe recovered samples were measured using a high-performance liquidchromatography-electron capture detector (HPLC-ECD) method at a flowrate of 0.25 ml/min, at a column temperature of 25° C., and at anapplied voltage of 400 mV, in which a mobile phase was 0.1 M phosphatebuffer (pH 6.0) and a Eicompak CA-b 50DS column (2.1φ×150 mm) attachedby a precolumn was used.

[0102] The results were shown in FIG. 11. It was suggested that Compound3 inhibited dopamine release in the nucleus accumbens projected form A10nerve terminals which related to a drug reward effect.

[0103] Referring to FIG. 11, a symbol * represents a level ofsignificance of not more than 5% and a symbol ** represents a level ofsignificance of not more than 1%, thereby indicating statisticalsignificance.

Industrial Applicability

[0104] A remedy for drug dependence in accordance with the presentinvention is a promising medicament with reduced adverse effects, whichinhibits development of psychic dependence, and also physical dependenceby inhibiting reward effects induced by dependence-producing drugs.

1. A remedy for drug dependence comprising an opioid κ receptor agonistas an active ingredient.
 2. A remedy for drug dependence according toclaim 1 , wherein the drug dependence is nicotine dependence.
 3. Aremedy for drug dependence according to claim 2 , wherein the opioid κreceptor agonist is a morphinan derivative or pharmacologicallyacceptable acid-addition salts thereof.
 4. A remedy for drug dependenceaccording to claim 3 , wherein the morphinan derivative or thepharmacologically acceptable acid-addition salts thereof is a compoundor pharmacologically acceptable acid-addition salts thereof representedby the following general formula (I):

 wherein . . . is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ isoptionally identical or different in the formula); B is a valence bond,a straight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group; R⁶ is a hydrogen atom; R⁷ is a hydrogenatom, a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms,or an alkanoyloxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl grouphaving from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5carbon atoms.
 5. A remedy for drug dependence according to claim 4 ,wherein in the general formula (I), R¹ is a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup; R² and R³ are, independently of each other, a hydrogen atom, ahydroxy group, an acetoxy group, or a methoxy group; A is —XC(═Y)—(wherein X is NR⁴, S, or O; Y is O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms), —XC(═Y)Z—, —X—, or —XSQ₂— (wherein X is NR⁴; Y is O or S; Z isNR⁴ or O; and R⁴ is a hydrogen atom, or a straight-chainor-branched-chain alkyl group having from 1 to 5 carbon atoms); B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,—C≡C—, —CH₂O— or —CH₂S—; R⁵ is the same as that in claim 4 ; R⁶ and R⁷are —O— together; and R⁸ is a hydrogen atom.
 6. A remedy for drugdependence according to claim 5 , wherein in the general formula (I), Ais —NR⁴C(═O)— or —NR⁴C(═O)O— (wherein R⁴is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms); B is a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, or —C≡C—; and R⁵ is a hydrogen atom or an organic grouphaving a basic skeleton selected from the group consisting of thefollowing formulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group.
 7. A remedy for drug dependence according toclaim 1 , wherein the drug dependence is cocaine dependence; and whereinthe opioid κ receptor agonist is a morphinan derivative or thepharmacologically acceptable acid-addition salts thereof represented bythe following general formula (I):

 wherein . . . is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ isoptionally identical or different in the formula); B is a valence bond,a straight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group; R⁶ is a hydrogen atom; R⁷ is a hydrogenatom, a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms,or an alkanoyloxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl grouphaving from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5carbon atoms.
 8. A remedy for drug dependence according to claim 7 ,wherein in the general formula (I), R¹ is a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup; R² and R³ are, independently of each other, a hydrogen atom, ahydroxy group, an acetoxy group, or a methoxy group; A is —XC(═Y)—(wherein X is NR⁴, S, or O; Y is O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms), —XC(═Y)Z—, —X—, or —XSO₂— (wherein X is NR⁴; Y is O or S; Z isNR⁴ or O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms); B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,—C≡C—, —CH₂O— or —CH₂S—; R⁵ is the same as that in claim 7 ; R⁶ and R⁷are —O— together; and R⁸ is a hydrogen atom.
 9. A remedy for drugdependence according to claim 8 , wherein in the general formula (I), Ais —NR⁴C(═O)— or —NR⁴C(═O)O— (wherein R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms); B is a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, or —C≡C—; and R⁵ is a hydrogen atom or an organic grouphaving a basic skeleton selected from the group consisting of thefollowing formulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group.
 10. A remedy for drug dependence accordingto claim 1 , wherein the drug dependence is opioid μ receptor agonistdependence; and wherein the opioid κ receptor agonist is a morphinanderivative or the pharmacologically acceptable acid-addition saltsthereof represented by the following general formula (I):

 wherein . . . is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R ² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ isoptionally identical or different in the formula); B is a valence bond,a straight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group is optionally substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group; R⁶ is a hydrogen atom; R⁷ is a hydrogenatom, a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms,or an alkanoyloxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl grouphaving from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5carbon atoms.
 11. A remedy for drug dependence according to claim 10 ,wherein in the general formula (I), R¹ is a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup; R² and R³ are, independently of each other, a hydrogen atom, ahydroxy group, an acetoxy group, or a methoxy group; A is —XC(═Y)—(wherein X is NR⁴, S, or O; Y is O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms), —XC(═Y)Z—, —X—, or —XSO₂— (wherein X is NR⁴; Y is O or S; Z isNR⁴ or O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms); B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,—C≡C—, —CH₂O— or —CH₂S—; R⁵ is the same as that in claim 10 ; R⁶ and R⁷are —O— together; and R⁸ is a hydrogen atom.
 12. A remedy for drugdependence according to claim 11 , wherein in the general formula (I), Ais —NR⁴C(═O)— or —NR⁴C(═O)O— (wherein R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms); B is a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, or —C≡C—; and R⁵ is a hydrogen atom or an organic grouphaving a basic skeleton selected from the group consisting of thefollowing formulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a-trifluoromethoxy group,and a methylenedioxy group.
 13. A dopamine-release inhibitor, comprisingan opioid κ agonistic morphinan derivative or pharmacologicallyacceptable acid-addition salts thereof as an active ingredientrepresented by the following general formula (I):

 wherein . . . is a double bond, or a single bond; R¹ is an alkyl grouphaving from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbonatoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl grouphaving from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5carbon-atoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴is optionally identical or different in the formula); B is a valencebond, a straight-chain or branched-chain alkylene group having from 1 to14 carbon atoms (wherein the alkylene group is optionally substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupis optionally replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups), or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms (wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups); and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

Organic Groups Represented by R⁵ wherein the organic group-optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group; R⁶ is a hydrogen atom; R⁷ is a hydrogenatom, a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms,or an alkanoyloxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl grouphaving from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5carbon atoms.
 14. A dopamine-release inhibitor according to claim 13 ,wherein in the general formula (I), R¹ is a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup; R² and R³ are, independently of each other, a hydrogen atom, ahydroxy group, an acetoxy group, or a methoxy group; A is —XC(═Y)—(wherein X is NR⁴, S, or O; Y is O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms), —XC(═Y)Z—, —X—, or —XSO₂— (wherein X is NR⁴; Y is O or S; Z isNR or O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms); B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,—C≡C—, —CH₂O— or —CH₂S—; R⁵ is the same as that in claim 13 ; R⁶ and R⁷are —O— together; and R⁸ is a hydrogen atom.
 15. A dopamine-releaseinhibitor according to claim 14 , wherein in the general formula (I), Ais —NR⁴C(═C)— or —NR⁴C(═O)O— (wherein R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms); B is a straight-chain alkylene group having from 1 to 3 carbonatoms, —CH═CH—, or —C≡C—; and R⁵ is a hydrogen atom or an organic grouphaving a basic skeleton selected from the group consisting of thefollowing formulas:

Organic Groups Represented by R⁵ wherein the organic group optionallyhave at least one substituent selected from the group consisting of analkyl group having from 1 to 5 carbon atoms, an alkoxy group having from1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbonatoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group.
 16. A dopamine-release inhibitor accordingto claim 15 , wherein diseases to be treated include nicotinedependence, cocaine dependence, opioid μ receptor agonist dependence,alcohol dependence, stimulant dependence, central nervous systemsedative dependence, and hallcinogen dependence.